The present invention provides a novel composition for nasal insufflation which provides a means for the administration of the extracellular portion of the Intercellular Adhesion Molecule (sICAM-1).
The sICAM-1 molecule and its antiviral effects are disclosed in EPA 391088-A and U.S. Application Ser. No. 08/479,557, filed Jun. 7, 1995 which are incorporated by reference. ICAM-1 is disclosed in U.S. 5,284,931, which is incorporated by reference. This drug is active as a competitive antagonist for rhinovirus binding. The intranasal administration of sICAM-1 is mentioned in Ser. No. 07/514,033 but the concept of formulating sICAM-1 as an insufflate for nasal administration is not disclosed. Various diluents are mentioned for use in preparing controlled release pharmaceutical compositions of sICAM-1 including carboxymethylcellulose but there is no disclosure of the use of any concentration of carboxymethylcellulose sodium salt or of the concept of formulating a long acting nasal insufflate.
The normal nasal residence time for most drugs that are placed in the nasal passages is from 15 to 20 minutes. The residue of any drug that is not systemically absorbed through the nasal membranes is cleared to the posterior portion of the nasopharynx and swallowed by the patient. The relatively large molecular weight of sICAM-1 (82,000 daltons) prevents the systemic absorption of any substantial amount of the drug from the nasal passages.
Insufflates are generally recognized as finely divided powders that are directly introduced into a body cavity by means of an insufflator or powder blower to achieve a local or systemic effect. Insufflates may also be administered from a pressurized aerosol which provides accurate control of the dose which is administered by using a metered aerosol valve. In order to administer, by insufflation, a drug which is intended to have a local effect in the nasopharynx, it is necessary to formulate the drug in a solid diluent which is pharmaceutically acceptable and does not interfere with the dispersion of the drug, does not interfere with the adhesion of the drug to the mucus membranes, does not have an adverse effect on the shelf life of the drug and is not excessively hygroscopic so that it may cause the formation of large particles in the composition during storage under ambient conditions. For these reasons it is desirable to provide a stable sICAM-1 therapeutic composition which will enhance the retention of the protein in the nasal passages.
The applicant has discovered a novel composition for the intranasal administration of sICAM-1 which is based on the use of a carrier system which comprises carboxymethylcellulose sodium as a solid diluent for the sICAM-1.
Accordingly, it is a primary object of this invention to provide a dry composition of sICAM-1 which is suitable for administration by insufflation.
It is also an object of this invention to provide a dry composition of sICAM-1 which does not interfere with the dispersion of the drug.
It is also an object of the invention to provide a dry composition of sICAM-1 which promotes the adhesion of the drug to the mucus membranes.
It is also an object of the invention to provide a dry composition of sICAM-1 which does not have an adverse effect on the shelf life of the drug.
It is also an object of the invention to provide a dry composition of sICAM-1 which is not excessively hygroscopic so that it may cause the formation of agglomerates in the composition during storage under ambient conditions.
It is also an object of the invention to provide a dry composition of sICAM-1 which is compatible with a hard gelatin capsule.
These and other objects of the invention will become apparent from a review of the appended specification.
The invention provides a finely divided, dry powdered pharmaceutical composition adapted to be administered as an insufflate, said dry powdered pharmaceutical composition comprising:
(a) an therapeutically effective amount of sICAM-1;
(b) an amount of carboxymethyl cellulose which is effective to retain sICAM-1 on the intranasal membranes;
(c) an amount of a bulking agent to produce a pharmaceutically elegant product which is effective to prevent the collapse of the carboxymethylcellulose and the sICAM-1 during lyophylization.
The formulation will be prepared to provide a delivered dose of from 0.1 to 1.0 mg and preferably from 0.05 to 75 mg of sICAM-1 to the intranasal passages by the introduction of one single inhalation of the insufflate.
sICAM-1 is a genetically engineered form of the extracellular portion of the sICAM-1 receptor and as such acts as a competitive antagonist for rhinovirus binding to host cells. This material is also known as BIRR 4 and is a single chain recombinant, soluble glycoprotein derived by genetic engineering from a naturally occurring transmembrane glycoprotein sICAM-1. BIRR 4 is a truncated form of the intercellular adhesion molecule 1(ICAM-1) containing the amino acids that comprise the extracellular domain of the molecule. Based on DNA, sequence analysis, BIRR 4 is predicted to contain five immunoglobulin-like domains stabilized by intrachain disulfide bonds.
The premise in using sICAM-1 in the prevention and/or early treatment of the common cold is based on the fact that the sICAM-1 compound will prevent the rhinovirus from becoming attached to the mucous membrane of the nose. In order to protect the nasal membranes from the rhinovirus, it is desirable to substantially completely contact the nasal mucous membranes with the sICAM-1 molecule in order that the sICAM-1 molecule will be distributed across the mucous membrane surface where it will interact with any rhinovirus particles that may be present in the nasal passages and prevent or attenuate the clinical progress of any infection. The intended hosts for treatment with the product of the invention include primates such as humans who may be treated to relieve the symptoms of a rhinovirus infection or for the prophylaxis of a rhinovirus infection.
The applicants have discovered that the use of carboxymethylcellulose sodium as a carrier for sICAM-1 provides an insufflate which extends the action of sICAM-1 in the nasal passages as compared to compositions which are based on aqueous solutions of sICAM-1 or which are insufflates of sICAM-1 that are based on the use of hydroxypropyl cellulose or hydroxyethylcellulose. In addition, the applicant has discovered that the addition of a bulking agent which may be a sugar alcohol such as sorbitol, mannitol or galactitol, or an amino acid such as glycine or a polymer such as a carbohydrate based polymer which may be dextran or cyclodextrin to the sICAM-1 combination with carboxymethylcellulose sodium will provide a bulking effect without exerting a significant effect on the retention of the sICAM-1 on the nasal passages.
The particular carboxymethyl cellulose sodium used in the invention will be a pharmaceutical grade that will have a minimum purity of 99.5%. Generally the preferred carboxymethyl cellulose sodium will have a viscosity in water of 150 to 250 cps when measured at a temperature of 25xc2x0 C. and a concentration of 1 wt %. If desired, carboxy methylcelluloses having different molecular weights may be blended together to obtain a product having a desired viscosity.
The composition of the invention will also include inorganic salts which will provide a buffered pH of about 6.0. Generally, an alkali metal chloride such as sodium or potassium chloride is combined with sodium monobasic phosphate and the pH is adjusted with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.
The insufflate is preferably made by dissolving the components in water and removing the water by lyophilization and passing the product of lyopilization through an appropriately sized sieve to provide a free flowing powder which is finely divided and suitable for administration using a suitable inhaler.
The method in which the powder components are combined to form the lyophillizable composition is important because if the powders are not combined according to the following procedure, the biological activity of the sICAM-1 may be adversely affected. It is preferred to prepare a solution of the sICAM-1 in the phosphate buffer by dialyzing the sICAM-1 from the solution in which sICAM is produced into the phosphate buffer solution using a polysulfone diafiltration membrane. A solution of the carboxy methyicellulose sodium and the bulking agent are separately prepared by dry blending the powdered components prior to dispersing the mixed components in water at 45 to 55xc2x0 C. and preferably at about 50xc2x0 C. The dry blending of the bulking agent and the carboxymethyl cellulose sodium facilitates the wetting of the carboxymethyl cellulose sodium and minimizes the aggregation of the polymer when it is dispersed in water. After the powders are combined with water, it is preferred to employ a high shear mixing apparatus such as a Waring blender for 2 to 10 minutes to disperse the, powders in the water. The dispersed mixture is then filtered through an appropriate filter e.g 5 to 50 microns, and allowed to cool to room temperature.
After the polymer has cooled to room temperature, equal weights of the polymer solution and the sICAM-1 solution are mixed and placed in lyophilization vials. The vials are loaded into a lyophilizer and freeze dried.
Generally the compositions which are prepared for lyophilization will contain:
The dry powdered pharmaceutical composition will include in weight %:
The preferred dry powdered pharmaceutical composition will include in weight %:
Generally it will be preferred to package a single therapeutic dose of the powder in two piece hard gelatin capsules which may be opened just prior to use. Each capsule may contain from 5 to 20 mg of composition with from 0.01 to 1.0 mg of sICAM-1. The powder is placed directly in an inhaler or the intact capsule may be placed in an inhaler which is adapted to open the capsule and to expel the powder contents of the capsule in a form where it is mixed with air and may be directly inspired into the patient""s nose.
For use in this type of an inhaler, the gelatin capsule should have hemispherical ends which interact with the inhaler to provide for proper dispensing of the powder. An example of a useful apparatus for the practice of the invention is described in U.S. Pat. No. 4,889,114, which is incorporated by reference. That apparatus may be provided with a nasal tip such as a DeVilbiss nasal tip, Model 40-TR,